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United States Patent |
5,034,406
|
Gluchowski
|
July 23, 1991
|
Method for reducing or maintaining intraocular pressure
Abstract
A method of reducing or maintaining intraocular pressure in a mammalian
eye, e.g., affected with glaucoma, is disclosed. This method comprises
administering directly to the mammalian eye an effective amount of one or
more 2-cycloalkylamino oxazolines, salts thereof, bases thereof and
mixtures thereof.
Inventors:
|
Gluchowski; Charles (Mission Viejo, CA)
|
Assignee:
|
Allergan, Inc. (Irvine, CA)
|
Appl. No.:
|
412528 |
Filed:
|
September 26, 1989 |
Current U.S. Class: |
514/377; 514/913 |
Intern'l Class: |
A61K 043/76 |
Field of Search: |
514/377,913
|
References Cited
U.S. Patent Documents
3598833 | Aug., 1971 | Hiltmann et al.
| |
3676798 | Jul., 1972 | Guilk et al. | 514/377.
|
4861760 | Aug., 1989 | Mazuel et al. | 514/912.
|
Foreign Patent Documents |
675645 | Sep., 1967 | ZA.
| |
Other References
Review: A Synopsis of Recent Developments in Antiglaucoma Drugs, Marsha A.
McLaughlin and George C. Y. Chiou.
Editorial: Intraocular Pressure and Glaucoma, Alfred Sommer.
German Article: Stereochemische Untersuchungen uber Arzneimittel. 4 Mitt.
(*) Konformation and antihypertensive Wirksamkeit von
2-(2,6-Dialkycyclohexyl)-amino-2-oxazolinen (**) Hiltmann, Kurz, Wollweber
and Stoepel.
|
Primary Examiner: Friedman; Stanley J.
Assistant Examiner: Fay; Zohreh A.
Attorney, Agent or Firm: Peterson; Gordon L., Uxa, Jr.; Frank J.
Claims
I claim:
1. A method for reducing or maintaining the intraocular pressure in a
mammalian eye comprising administering directly to a mammalian eye in an
amount effective to reduce or maintain the intraocular pressure in the
mammalian eye of a compound selected from the group consisting of:
##STR7##
wherein R.sub.1 is selected from the group consisting of alkyl radials
containing 1 to 3 carbon atoms, R.sub.2 is selected from the group
consisting of H and alkyl radicals containing 1 to about 5 carbon atoms, n
is an integer in the range of 2 to 4, each x is independently selected
from the integers 1 and 2, and each of the carbon atoms in the hydrocarbon
ring has 4 bonds associated therewith; (1) in which the hydrocarbon ring
includes a double bond in a position other than the alpha-beta position;
salts thereof; bases thereof and mixtures thereof.
2. The method of claim 1 wherein said compound is administered directly to
the mammalian eye in an amount effective in reduce the intraocular
pressure in the mammalian eye.
3. The method of claim 1 wherein said administering includes at least one
of applying said compound topically to the mammalian eye and injecting
said compound directly into the mammalian eye.
4. The method of claim 1 wherein said compound is administered in the form
of a mixture with an ophthalmically acceptable carrier.
5. The method of claim 4 wherein said mixture is a liquid at the time of
said administering.
6. The method of claim 4 wherein said compound is present in said mixture
in an amount in the range of about 0.0001% to about 1% (W/V).
7. The method of claim 4 wherein said compound is present in said mixture
in an amount in the range of about 0.05% to about 0.5% (W/V).
8. The method of claim 1 wherein the mammalian eye is affected with
glaucoma.
9. The method of claim 1 wherein n is equal to 3.
10. The method of claim 1 wherein said compound is selected from the group
consisting of (1), salts thereof, bases thereof and mixtures thereof.
11. The method of claim 10 wherein (1) has the following formula:
##STR8##
12. The method of claim 1 wherein R.sub.2 is H.
13. The method of claim 11 wherein R.sub.2 is H.
14. The method of claim 1 wherein said compound is a mixture of
enantiomers.
15. The method of claim 13 wherein said compound is a mixture of
enantiomers.
16. The method of claim 1 wherein R.sub.1 is trans relative to the amino
oxazoline group of (1).
17. The method of claim 11 wherein R.sub.1 is trans relative to the amino
oxazoline group of (1).
18. The method of claim 13 wherein R.sub.1 is trans relative to the amino
oxazoline group of (1).
19. The method of claim 1 wherein said compound has the following formula:
##STR9##
20. The method of claim 19 wherein said compound is a mixture of
enantiomers.
21. The method of claim 1 wherein said compound has the following formula:
##STR10##
22. The method of claim 21 wherein said compound is a mixture of
enantiomers.
23. The method of claim 1 wherein said compound has the following formula:
##STR11##
24. The method of claim 23 wherein said compound is a mixture of
enantiomers.
25. The method of claim 1 wherein said compound has the following
structure:
##STR12##
26. The method of claim 25 wherein said compound is a mixture of
enantiomers.
Description
BACKGROUND OF THE INVENTION
The present invention relates to a method for reducing or maintaining
intraocular pressure. More particularly, it relates to a method for
reducing or maintaining intraocular pressure involving the administration
of an effective amount of a 2-cycloalkylamino oxazoline and/or a salt
thereof and/or a base thereof, e.g., in an opthalmically acceptable
carrier.
The method of the present invention is particularly useful for the
management of glaucoma, a disease of the eye characterized by increased
intraocular pressure. On the basis of its etiology, glaucoma has been
classified as primary or secondary. For example, primary glaucoma in
adults may be either chronic open-angle or acute or chronic angle-closure.
Secondary glaucoma results from pre-existing ocular diseases such as
uveitis, intraocular tumor or an enlarged cataract.
The underlying causes of primary glaucoma are not yet well known. The
increased intraocular pressure is due to obstruction of aqueous humor
outflow. In chronic open-angle glaucoma, the anterior chamber and its
anatomic structures appear normal, but drainage of the aqueous humor is
impeded. In acute and chronic angle-closure glaucoma, the anterior chamber
is shallow, the filtration angle is narrowed and the iris may obstruct the
trabecular meshwork at the entrance to the canal of Schlemm. Dilation of
the pupil may push the root of the iris forward against the angle or may
produce pupillary block and thus precipitate an acute attack. Eyes with
narrow anterior chamber angles are predisposed to acute angle-closure
glaucoma attacks of varying degrees of severity.
Secondary glaucoma is caused by any interference with the flow of aqueous
humor from the posterior chamber into the anterior chamber and,
subsequently, into the canal of Schlemm. Inflammatory disease of the
anterior segment may prevent aqueous escape by causing complete posterior
synechia in iris bombe, and may plug the drainage channel with exudates.
Other common causes are intraocular tumors, enlarged cataracts, central
retinal vein occlusion, trauma to the eye, operative procedures and
intraocular hemorrhage.
Considering all types together, glaucoma occurs in about 2% of all persons
over the age of 40 and may be asymptomatic for years before progressing to
rapid loss of vision. In cases where surgery is not indicated, topical
beta-adrenoceptor antagonists have traditionally been the drugs of choice
for treating glaucoma
Hiltmann et al U.S. Pat. No. 3,598,833 discloses 2-cycloalkylamino
oxazolines as having local anesthetic properties, sedative properties,
vasoconstrictory effects, mucous membrane deswelling properties, blood
pressure depressant effects, and inhibitory effects on the secretion of
gastric fluid. None of these properties and effects involve administering
the 2-cycloalkylamino oxazoline directly to the eye. Further, there is no
suggestion in the Hiltmann et al patent that such compounds are useful in
reducing or maintaining intraocular pressure.
SUMMARY OF THE INVENTION
A new method for reducing or maintaining the intraocular pressure in a
mammalian eye has been discovered. This method comprises administering
directly to a mammalian eye an effective amount of one or more
2-cycloalkylamino oxazolines (as defined herein), salts thereof, bases
thereof and mixtures thereof This new method is particularly effective in
the treatment or management of mammalian, e.g., human, eyes affected with
glaucoma.
DETAILED DESCRIPTION OF THE INVENTION
The 2-cycloalkylamino oxazolines, salts thereof and bases thereof which are
administered directly to a mammalian eye in the present method are those
which are effective to reduce or maintain, preferably to reduce, the
intraocular pressure in the mammalian eye. The effective compounds are
selected from the group consisting of:
##STR1##
wherein R.sub.1 is selected from the group consisting of alkyl radials
containing 1 to 3 carbon atoms, R.sub.2 is selected from the group
consisting of H and alkyl radicals containing 1 to 5 carbon atoms, n is an
integer in the range of 2 to 4, each x is independently selected from the
integers 1 and 2, and each of the carbon atoms in the hydrocarbon ring has
4 bonds associated therewith; (1) in which the hydrocarbon ring includes
one double bond in a position other than the alpha-beta position; salts
thereof; bases thereof and mixtures thereof. All stereoisomers, tautomers
and mixtures thereof which comply with the constraints of one or more
formulae of the presently useful compounds set forth herein are included
within the scope of the present invention.
The present method is particularly effective in a strategy for the
treatment or management of glaucoma, whether primary or secondary glaucoma
In this embodiment, one or more of the presently useful compounds are
preferably administered directly to a mammalian eye affected with glaucoma
to effectively reduce or maintain, preferably control, the intraocular
pressure in the glaucoma-affected eye.
Although the hydrocarbon ring of the presently useful compounds may include
5, 6 or 7 carbon atoms, it is preferred that this ring contain 6 carbon
atoms. Thus, with regard to the above-noted structural formulae, n is
preferably 3. Also, this ring may include one double bond at a position
other than the alpha-beta position However, it is preferred that the
hydrocarbon ring be completely saturated.
In one particularly useful embodiment, the R.sub.2 group is situated on the
last carbon atom of the hydrocarbon ring. For example, with regard to a 6
member hydrocarbon ring, compound (1) preferably has the following
formula:
##STR2##
Although both R.sub.1 and R.sub.2 can be alkyl radicals, very useful
reductions in intraocular pressure are obtained using compounds in which
R.sub.1 is an alkyl radical and R.sub.2 is an H radical.
Quite often the presently useful compounds are present as a mixture of
enantiomers or optical isomers. While there are differences in activity,
e.g., intraocular pressure reducing activity, between optical isomers,
such differences often do not warrant the effort and expense required to
produce or separate an individual optical isomer. Thus, a mixture of
enantiomers is useful even where there is a difference in the activities
of the individual enantiomers. However, each individual enantiomer having
the requisite activity is useful in the present method and is included
within the scope of the present invention.
Regarding geometric isomerism it is preferred that the R.sub.1 group be
trans relative to the amino oxazoline group of (1) above. In the event
that the R.sub.1 and R.sub.2 groups are both alkyl groups and R.sub.2 is
situated on the last carbon atom of the hydrocarbon ring, it is preferred
that both R.sub.1 and R.sub.2 be trans relative to the amino oxazoline
group of (1) above. Such trans isomers have been found to be particularly
effective in reducing intraocular pressure. In certain instances, the
corresponding cis isomers have little or no intraocular pressure reducing
activity. Therefore, it may be advantageous to selectively produce or
separate one or more geometric isomers, e.g., the above-noted trans
isomers, in order to obtain the desired intraocular pressure reducing
activity.
The presently useful compounds are often administered to the eye in the
form of a mixture with an ophthalmically acceptable carrier. Any suitable,
e.g., conventional, ophthalmically acceptable carrier may be employed.
Such a carrier is ophthalmically acceptable if it has substantially no
long term or permanent detrimental effect on the eye to which it is
administered. Examples of ophthalmically acceptable carriers include
water, in particular distilled water, saline and the like aqueous media.
The presently useful compounds are preferably administered to the eye as a
liquid mixture with the carrier. The compounds are more preferably soluble
in the carrier so that the compounds are administered to the eye in the
form of a solution.
When an ophthalmically acceptable carrier is employed, it is preferred that
the mixture contain one or more of the presently useful compounds in an
amount in the range of about 0.0001% to about 1%, more preferably about
0.05% to about 0.5%, W/V.
Any method of administering drugs directly to a mammalian eye may be
employed to provide the presently useful compound or compounds to the eye
to be treated. By the term "administering directly" is meant to exclude
those general systemic drug administration modes, e.g., injection directly
into the patients blood vessels, oral administration and the like, which
result in the compound or compounds being systemically available. The
primary effect on the mammal resulting from the direct administering of
the presently useful compound or compounds to the mammal's eye is
preferably a reduction in intraocular pressure. More preferably, the
presently useful compound or compounds are applied topically to the eye or
are injected directly into the eye. Particularly useful results are
obtained when the compound or compounds are applied topically to the eye.
Topical ophthalmic preparations, for example ocular drops, gels or creams,
are preferred because of ease of application, ease of dose delivery, and
fewer systemic side effects, such as cardiovascular hypotension. An
exemplary topical ophthalmic formulation is shown below in Table I. The
abbreviation q.s. means a quantity sufficient to effect the result or to
make volume.
TABLE I
______________________________________
Ingredient Amount (% W/V)
______________________________________
2-Cycloalkylamino oxazoline
about 0.0001 to about 1.0
Preservative 0-0.10
Vehicle 0-40
Tonicity Adjustor 1-10
Buffer 0.01-10
pH Adjustor q.s. pH 4.5-7.5
antioxidant as needed
Purified Water as needed to make 100%
______________________________________
Various preservatives may be used in the ophthalmic preparation described
in Table I above. Preferred preservatives include, but are not limited to,
benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate,
and phenylmercuric nitrate. Likewise, various preferred vehicles may be
used in such ophthalmic preparation. These vehicles include, but are not
limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose,
poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose, and purified
water.
Tonicity adjustors may be added as needed or convenient. They include, but
are not limited to, salts, particularly sodium chloride, potassium
chloride, mannitol, and glycerin, or any other suitable ophthalmically
acceptable tonicity adjustor.
Various buffers and means for adjusting pH may be used so long as the
resulting preparation is ophthalmically acceptable. Accordingly, buffers
include, but are not limited to, acetate buffers, citrate buffers,
phosphate buffers, and borate buffers. Acids or bases may be used to
adjust the pH of these formulations as needed.
In a similar vein, ophthalmically acceptable antioxidants include, but are
not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine,
butylated hydroxyanisole, and butylated hydroxytoluene.
Other excipient components which may be included in the exemplary
ophthalmic preparation described in Table I are chelating agents which may
be added as needed. The preferred chelating agent is edetate disodium,
although other chelating agents may also be used in place of or in
conjunction with it.
The presently useful 2-cycloalkylamino oxazolines may be prepared by
reacting 2-cycloalkyl-isocyanide dichlorides of the formula:
##STR3##
with ethanolamine in organic solvents or in water, and if desired, with
the addition of a base such as triethylamine, sodium carbonate or sodium
hydroxide at a temperature of from 0.degree. C. to 100.degree. C.
Alternatively, these compounds can be prepared by cyclizing reactive
esters of N'-cycloalkyl 1-N'-beta-hydroxy-ethyl-ureas of the formula:
##STR4##
by heating in water, optionally at temperatures above 100.degree. C. under
pressure and precipitating the bases by means of ammonia from the
resultant aqueous solution of the 2-cycloalkylamino oxazoline salts
formed. Additionally, N'-cycloalkyl 1-N'-beta-chloro-ethyl-ureas of the
formula
##STR5##
can be cyclized by heating, in an aqueous suspension or in refluxing
ethanol solvent, to form the corresponding 2-cycoalkylamino oxazolines.
R.sub.1, R.sub.2,x and n have the meanings set forth above. The
hydrocarbon ring may contain a double bond, with the proviso that if there
is a double bond, such is not in the alpha-beta position. Such compounds
which include a double bond may be prepared by methods analogous to those
given above.
If desired the salts so obtained can be converted into the free bases by
means of a base such as a sodium hydroxide solution or ammonia.
A more detailed description of certain methods for the synthesis of the
presently useful compounds is set forth in Hiltmann et al U.S. Pat. No.
3,598,833 which is hereby incorporated in its entirety by reference
herein.
The following non-limiting examples illustrate certain aspects of the
present invention.
EXAMPLES 1 TO 8
A series of eight (8) 2-cycloalkylamino oxazolines were selected for
testing. These materials, each except for the material used in Examples 7
and 8 being a mixture of enantiomers, were as follows:
##STR6##
In addition the individual enantiomers of the mixture tested in Example 5
were tested These individual enantiomers are identified as (+) enantiomer
(Example 5A) and (-) enantiomer (Example 5B).
Each of these materials was dissolved in distilled water at a concentration
of 0.1% (W/V). Each of these solutions was administered topically and
unilaterally to one eye of a drug-naive, unanesthetized New Zealand white
rabbit in a single 50 micro liter drop. The contralateral eye received an
equal volume of saline prior to determining the intraocular pressure after
the mixture was administered. Also, approximately 10 micro liters of 0.5%
(W/V) proparacaine (topical anesthetic) was applied to the corneas of each
of the rabbits before determining intraocular pressure. As a control test,
six (6) other drug-naive, unanesthetized New Zealand white rabbits were
treated and tested as described above except that no 2-cycloalkylamino
oxazoline was included in the solutions administered to the eyes.
The intraocular pressure was determined in both eyes of each rabbit both
before and after the solutions were administered. Such intraocular
pressure determinations were made in the conventional manner using
conventional equipment.
Results of these IOP determinations were as follows:
______________________________________
Maximum Difference in Intraocular
Pressure After Solution Administration
mm Hg
Ipsilateral Contralateral
Example (Treated) Eye
(Untreated) Eye
______________________________________
Control N.S. N.S.
1 -3.8 .+-. 0.9
-6.6 .+-. 0.9
2 N.S. N.S.
3 -2.4 .+-. 0.8
-3.3 .+-. 1.2
4 N.S. N.S.
5 -5.0 .+-. 1.3
-5.4 .+-. 1.4
5A -6.6 .+-. 1.6
-5.5 .+-. 1.0
5B -3.2 .+-. 0.6
-3.0 .+-. 0.3
6 -6.0 .+-. 1.1
-8.3 .+-. 1.6
7 N.S. N.S.
8 N.S. N.S.
______________________________________
N.S. refers to no significant change in the intraocular pressure.
These results demonstrate the effectiveness in reducing intraocular
pressure achieved by directly administering 2-cycloalkylamino oxazolines
to mammalian eyes. Particularly useful results, Examples 1, 3, 5, 5A, 5B
and 6, were obtained using 2-cycloalkylamino oxazolines in which the alkyl
substituent group or groups on the hydrocarbon ring is trans relative to
the amino oxazoline group. In addition, at least with regard to certain
mammalian eyes, e.g., New Zealand white rabbit eyes, the intraocular
pressure in the contralateral eye is also reduced, often to a greater
extent then observed in the ipsilateral eye. Examples 5A and 5B
demonstrate that both of the individual enantiomers have intraocular
pressure reducing activity, although to differing degrees. Further, the
2-cycloalkylamino oxazoline mixture used in Example 6 was found to be
particularly useful in reducing intraocular pressure while having less
sedative effect than the mixtures used in Examples 1, 3 and 5. The results
of these tests demonstrate that 2-cycloalkylamino oxazolines can be
directly administered to mammalian eyes to reduce or maintain intraocular
pressure, e.g., in the treatment of mammalian eyes affected with glaucoma.
While this invention has been described with respect to various specific
examples and embodiments, it is to be understood that the invention is not
limited thereto and that it can be variously practiced within the scope of
the following claims.
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